Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is only 15%. As existing therapies do not significantly increase survival rate, there is an urgent need to develop newer therapies that can augment the existing treatments. The goal of the proposed work is to produce a safe and effective targeted chemotherapy for the treatment of non-small cell lung cancer (NSCLC). To this end, a rapidly internalizing, humanized, anti-EGP-1 MAb, hRS7, linked to a potent topoisomerase 1 inhibitor, SN-38, was designed and evaluated in the SBIR Phase I study. The immunoconjugate, which was designed to allow for the intact intratumoral liberation of the drug, maintained its antigen-binding property and drug potency, and produced significant and specific therapeutic efficacy in a nude mouse model of lung adenocarcinoma. In addition, a 7-fold greater dose than that used for therapy was nontoxic. The drug component is the pharmacologically active form of an already approved cancer drug, CPT-11, which is advantageous in that the safety issues related to the drug are already well documented. The successful SBIR Phase I feasibility research portends a high potential for translation to novel therapeutic strategies. The Phase II program will focus on cGMP manufacture and expanded preclinical studies. Specifically, the conjugate manufacture will be optimized, its storage format will be finalized, and a non-GMP lot (2 g) and two cGMP lots (2W5 g) of the conjugate will be prepared and evaluated for shelf-life stability. The product will be evaluated in a second model of non-small cell lung cancer and a CPT-11-refractory model, tested for potential immunogenicity due to the drug and the linker, and assessed for therapeutic window and toxicity in nude mice. Most importantly, the product safety will be determined in a non-human primate species, which will delineate the safe starting dose in human. Finally, an Investigational New Drug application will be submitted to the FDA for approval to start a clinical Phase I dose-escalation trial in NSCLC patients in the SBIR Phase III period. PUBLIC HEALTH RELEVANCE: Lung cancer is one of the most common malignancies worldwide, and the 5-year survival rate is just 15%. Continued efforts with newer therapies are urgently needed. The ultimate goal of the proposed project is to develop a safer and more efficacious targeted chemotherapy of non-small cell lung cancer using a tumor-selective monoclonal antibody and the highly potent form of the cancer drug, CPT-11.